The long-term objective of this proposal is to contribute to the understanding of the initial development of the human cerebral cortex. Normal development of the cerebral cortex is essential for proper functioning of the adult brain, while its disruption results in various neurodevelopmental disorders, manifested by mental retardation, ectopias, and epilepsy. In order to understand these neurological disorders, there is a need to study human brain development. The overriding hypothesis to be tested is that progenitor cells in human brain are a diverse population of cells that emerged during evolution, and that this diversity is essential for the complex structure and function of the human cerebral cortex. Thus, evaluation of species specific differences between model systems and humans is necessary,as our ultimate goal is to prevent and cure human diseases. Data generated through this research will advance our understanding of both normal development, and of possible mechanisms that contribute to congenital brain malformations. In addition, our studies are expected to establish a prerequisite set of baseline data for proper diagnosis and treatment of pediatric brain disorders Specifically, we propose to study the contribution of progenitor cells during early and late corticogenesis in the human brain. Recently radial glia cells in rodent cerebral cortex have been demonstrated to be multiple progenitors that give rise to majority of pyramidal neurons. In human brain, this still has not been shown. We hypothesize that a larger repertoire of cortical progenitors in humans may in part explain the unique complexity of the human cerebral cortex. We propose to address some of the most controversial and pressing issues related to generation of human cortical neurons using immunocytochemistry, electron microscopy, in vitro systems, and electrical recordings. We would like to know the answers to the following questions: (1) Do all progenitor cells belong to radial glia or instead restricted types of neuronal progenitors coexist with radial glia at the onset of neurogenesis? (2) What are molecular and functional characteristics of intermediate progenitors in humans? (3) Can environmental factors influence fate decisions of cortical progenitor cells? Having available to us a well-characterized collection of fetal brains, and an opportunity to obtain fresh tissue, we are in a favorable position to tackle these questions.